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Background and Aims Epidural analgesia is pivotal in labour pain management, yet the transient efficacy and adverse effects of local anesthetics (LAs) drive the need for adjuvants. This review evaluates the efficacy and safety of diverse adjuvant classes—opioids, α2-adrenoceptor agonists, cholinergic agonists, NMDA antagonists, GABA receptor agonists, and corticosteroids—in enhancing analgesia, prolonging duration, and minimizing LA-related toxicity, while prioritizing maternal and neonatal safety.Methods A systematic review of randomized controlled trials (RCTs) and meta-analyses (2010–2024) from PubMed, EMBASE, and Cochrane Library was conducted. Studies assessing adjuvants combined with LAs (e.g., ropivacaine, bupivacaine) were included. Outcomes analyzed included pain scores (VAS), analgesia duration, LA consumption, maternal side effects (hypotension, pruritus), and neonatal outcomes (Apgar scores).Results Opioids (fentanyl, sufentanil) provided rapid analgesia (onset <20 minutes) but increased pruritus risk (RR 2.5 vs. non-opioids). α2-agonists (dexmedetomidine) prolonged analgesia by 2–3 hours (MD: 145 minutes, 95% CI 120–170) but extended motor blockade (MD: 55 minutes). Corticosteroids (dexamethasone 4–8 mg) reduced LA requirements by 25% and delayed analgesia onset by 30 minutes, with minimal maternal side effects. NMDA antagonists (ketamine) and GABA agonists (midazolam) showed preliminary efficacy in reducing hyperalgesia but lacked robust obstetric safety data. Cholinergic agonists (neostigmine) demonstrated mixed results, with limited adoption due to nausea risks. Neonatal outcomes remained unaffected across all adjuvants.Conclusions Dexmedetomidine and dexamethasone emerge as optimal adjuvants, balancing prolonged analgesia with tolerable side effects. Opioids remain valuable for rapid relief but require pruritus management. Novel agents (NMDA/GABA agonists) warrant further investigation to establish safety profiles. Standardized dosing protocols and multimodal approaches integrating corticosteroids with traditional adjuvants may optimize labour analgesia while minimizing risks.